(PQ10) Do microbiota alter the epigenetic landscape in human genome

项目摘要 本申请是对RFA-CA-15-009的回应，旨在提出解决PQ-10的开创性方法 “微生物群如何影响对癌症治疗的反应？”人类生物学不再仅仅关注 人体细胞不同身体栖息地的微生物组现在被认为是人体的重要组成部分 生物学、发展、进化、健康和疾病。人体内内源性植物群的细菌 比人类细胞多至少一个数量级。大量的共生菌和致病菌 不同的身体栖息地形成微生物组。细菌，包括支原体，内化并定殖于人类 细胞，从而破坏免疫防御系统和抗生素治疗。支原体最小 和最简单的自我复制有机体。支原体有200多种， 细菌由于其微小的尺寸，有限的基因组和缺乏细胞壁而被称为细菌。细胞壁的缺失传达了一些 对支原体的独特性质，包括对青霉素的抗性和对溶解和渗透的敏感性 冲击.我们和其他人的数据表明支原体感染与某些癌症类型有关， 包括结肠直肠癌这表明支原体和肿瘤在体内可能共存， 影响对癌症治疗的反应，或者，可替代地，表明支原体感染产生了 通过受影响者的表观遗传重编程实现多步骤恶性转化的可能路线图 正常/干细胞。我们的工作假设是肠道中的慢性支原体感染最终导致 上皮细胞的表观遗传改变可能增加肿瘤转化的可能性。一个 另一种，但不是唯一的假设是，支原体感染加速了已经进行的 通过诱导额外的表观遗传异常来促进肿瘤发生。我们的目标是追求这一点 创新假设我们的R21计划基于我们大量的创新实验数据 表征表观遗传异常，这些异常通过以下方式引入人类基因组中： 支原体5-甲基胞嘧啶-DNA甲基转移酶。我们的具体目标是：（1）展示 在被M感染的宿主细胞中存在异常的从头基因组DNA甲基化。猪鼻，和（2） 确定猪鼻支原体和其他支原体种属的基因组物质在 肿瘤和正常人组织样品。我们有信心我们的研究将引领典范- 转移导致宿主-病原体相互作用，人类表观遗传学和癌症发病，我们的项目将 具有广泛的影响。此外，这些知识将导致新的诊断和预后 方法和治疗方案的患者在癌症发展的风险。

PROJECT SUMMARY This application is in response to RFA-CA-15-009 to propose pioneering approaches to addressing PQ–10 “How do microbiota affect the response to cancer therapies?” Human biology is no longer focused only on human cells. Microbiomes at different body habitats are now considered an essential component of human biology, development, evolution, health and disease. Bacteria of the endogenous flora in the human body outnumber human cells by at least one order of magnitude. A plethora of symbiotic and pathogenic bacteria in different body habitats form the microbiome. Bacteria, including mycoplasmas, internalize and colonize human cells, thereby subverting the immune defense system and antibiotic treatment. Mycoplasmas are the smallest and simplest self-replicating organisms. Over 200 species of mycoplasma are distinguished from ordinary bacteria by their minute size, limited genome, and lack of a cell wall. The absence of a cell wall conveys some unique properties to mycoplasma including their resistance to penicillin and sensitivity to lysis and osmotic shock. The data by us and others imply that mycoplasma infections are associated with some cancer types, including colorectal cancer. This suggests the possible co-existence of mycoplasmas and tumors in vivo that affects the response to cancer therapies, or, alternatively, indicates that mycoplasma infections create a possible roadmap to multi-step malignant transformation via epigenetic reprogramming of the affected normal/stem cells. Our working hypothesis is that chronic mycoplasma infection in the gut eventually leads to epigenetic alterations in epithelial cells that may enhance the likelihood for neoplastic transformation. An alternative, but not an exclusive hypothesis, is that the mycoplasma infection accelerates an already on-going tumorigenesis through the induction of additional epigenetic abnormalities. Our goals are to pursue this innovative hypothesis. Our R21 program is based on volumes of our innovative experimental data characterizing epigenetic abnormalities, which are aberrantly introduced in the human genome by mycoplasmal 5-methylcytosine-DNA methyltransferases. Our Specific Aims are: (1) Demonstrate the presence of the aberrant, de novo genomic DNA methylation in host cells infected by M. hyorhinis, and (2) Determine the incidence of the genomic material of Mycoplasma hyorhinis and other mycoplasma species in tumor and normal human tissue samples. We are confident that our proposed studies will lead to paradigm- shifting results in host-pathogen interactions, human epigenetics and cancer onset, and that our project will have wide-ranging ramifications. Additionally, this knowledge will lead to novel diagnostic and prognostic approaches and therapeutic regiments in patients at risk of cancer development.